Autophagy is a highly conserved and regulated process that targets proteins and damaged organelles for lysosomal degradation to maintain cell metabolism, genomic integrity, and cell survival. The role of autophagy in cancer is dynamic and depends, in part, on tumor type and stage. Although autophagy constrains tumor initiation in normal tissue, some tumors rely on autophagy for tumor promotion and maintenance. Studies in genetically engineered mouse models support the idea that autophagy can constrain tumor initiation by regulating DNA damage and oxidative stress. In established tumors, autophagy can also be required for tumor maintenance, allowing tumors to survive environmental stress and providing intermediates for cell metabolism. Autophagy can also be induced in response to chemotherapeutics, acting as a drug-resistance mechanism. Therefore, targeting autophagy is an attractive cancer therapeutic option currently undergoing validation in clinical trials.